FDA Approval in CLL, Recommendation in STS, Partial Hold on Cervical Cancer Trial, and More

Gina Columbus

Published: Sunday, Feb 03, 2019

Today-

An FDA approval in chronic lymphocytic leukemia, a recommendation in soft tissue sarcoma, a partial clinical hold on a cervical cancer trial, an application withdrawn in non–small cell lung cancer, and a European approval in ovarian cancer.

Welcome to OncLive News Network! I’m Gina Columbus.

The FDA has approved the combination of ibrutinib and obinutuzumab for the frontline treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The decision is based on results from the phase III iLLUMINATE trial, in which the combination demonstrated a 77% reduction in the risk of progression or death compared with chlorambucil plus obinutuzumab. At a median follow-up of 31 months, the independent review committee-assessed median progression-free survival was not reached versus 19 months for chlorambucil and obinutuzumab.

The FDA also updated the ibrutinib label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately 5-year follow-up data from the phase III RESONATE and RESONATE-2 trials.

Additional resuls of the international, open-label, randomized, phase III iLLUMINATE trial showed that patients with high-risk disease who were treated with the ibrutinib combination experienced an 85% reduction in the risk of progression or death. The IRC-evaluated overall response rate was 89% in ibrutinib/obinutuzumab arm versus 73% in the chlorambucil/obinutuzumab arm. Overall survival had not yet been reached in either arm.

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In advanced soft tissue sarcoma, the FDA has recommended that no new patients should be treated with the combination of olaratumab plus doxorubicin, following the negative results of the phase III ANNOUNCE trial.

The agency's statement follows the January 2019 announcement that olaratumab plus doxorubicin missed the ANNOUNCE trial’s primary endpoint of overall survival and did not confirm a clinical benefit for patients with advanced or metastatic STS compared with standard doxorubicin. The OS endpoint in the leiomyosarcoma subpopulation was also not met.

Moreover, the European Medicines Agency issued a similar recommendation based on the negative findings of the confirmatory trial, also stating that the combination of olaratumab and doxorubicin should not be administered in any new patients with advanced STS.

Both regulatory authorities made statements recommending that patients currently receiving olaratumab may continue to receive the treatment if they appear to be benefitting from it.

Results of ANNOUNCE, which was the confirmatory trial for the FDA approval of olaratumab in this setting, showed that there was no difference in OS between the 2 arms. The median OS was 20.4 months with olaratumab/doxorubicin and 19.7 months with doxorubicin. In the leiomyosarcoma subpopulation, the median OS was 21.6 months and 21.9 months for olaratumab/doxorubicin and doxorubicin, respectively.

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The FDA has placed a partial clinical hold on the phase III AIM2CERV trial exploring the use of axalimogene filolisbac in patients with high-risk locally advanced cervical cancer.

The communication from the agency cites that the partial hold has been put in place until additional information on chemistry, manufacturing, and control matters associated with AXAL, are received. There were no safety issues associated with the trial cited. Additionally, all patients currently enrolled will continue to receive treatment with the agent. However, no new patients can enroll in the trial until the hold is resolved.

Advaxis, the manufacturer of the immunotherapy agent, stated that it has already taken steps to provide the FDA with the requested information on AXAL in an effort to get the hold lifted in a timely manner.

In July 2018, the FDA previously lifted a clinical hold on a phase I/II study of AXAL in combination with durvalumab in patients with advanced, recurrent, or refractory cervical cancer and human papillomavirus-associated head and neck cancer.

The hold was initiated in March 2018 following a patient death related to acute respiratory failure after 9 months of AXAL treatment. Following the hold, Advaxis agreed to new guidelines for the early detection and treatment of rare adverse events, acute respiratory failure.

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In non–small cell lung cancer, Bristol-Myers Squibb withdrew its supplemental biologics license application for the combination of nivolumab and ipilimumab for the frontline treatment of patients with advanced disease with tumor mutational burden at least 10 mutations per megabase, following recent discussions with the FDA.

The agency initially accepted the application in June 2018 based on findings from the phase III CheckMate-227 trial, which showed that the 1-year progression-free survival rate was 43% for patients with high TMB assigned to the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy.

In October 2018, BMS submitted an exploratory overall survival analysis to the FDA from part 1 of the CheckMate-227 trial, which included a low TMB subgroup of patients with stage IV or recurrent NSCLC who had not received prior therapy.

With these updated data, the FDA extended the review period by 3 months, which made the new action date May 20, 2019. However, the new data showed no difference in survival outcomes between patients whose tumors had high or low levels of TMB.

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The European Commission has approved an expanded indication for maintenance rucaparib in adult patients with platinum-sensitive, relapsed, high-grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA status.

The decision is based on findings from the phase III ARIEL3 trial, in which rucaparib led to an investigator-assessed median progression-free survival of 10.8 months compared with 5.4 months with placebo across the entire study population. Also, the overall response rate with rucaparib was 18%.

Additional results showed that, in patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo. The median PFS with rucaparib in this population was 16.6 months versus 5.4 months with placebo. Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency or low to high loss of heterozygosity.

The FDA approved the PARP inhibitor in this setting in April 2018, also based on the ARIEL3 findings.

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This week, we sat down with Dr Neha Mehta-Shah, of the Washington University School of Medicine in St. Louis, to discuss peripheral T-cell lymphoma treatment and future directions.

That’s all for today.

Thank you for watching OncLive News Network! I’m Gina Columbus.

SELECTEDLANGUAGE

Today-

An FDA approval in chronic lymphocytic leukemia, a recommendation in soft tissue sarcoma, a partial clinical hold on a cervical cancer trial, an application withdrawn in non–small cell lung cancer, and a European approval in ovarian cancer.

Welcome to OncLive News Network! I’m Gina Columbus.

The FDA has approved the combination of ibrutinib and obinutuzumab for the frontline treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The decision is based on results from the phase III iLLUMINATE trial, in which the combination demonstrated a 77% reduction in the risk of progression or death compared with chlorambucil plus obinutuzumab. At a median follow-up of 31 months, the independent review committee-assessed median progression-free survival was not reached versus 19 months for chlorambucil and obinutuzumab.

The FDA also updated the ibrutinib label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately 5-year follow-up data from the phase III RESONATE and RESONATE-2 trials.

Additional resuls of the international, open-label, randomized, phase III iLLUMINATE trial showed that patients with high-risk disease who were treated with the ibrutinib combination experienced an 85% reduction in the risk of progression or death. The IRC-evaluated overall response rate was 89% in ibrutinib/obinutuzumab arm versus 73% in the chlorambucil/obinutuzumab arm. Overall survival had not yet been reached in either arm.

***********************************

In advanced soft tissue sarcoma, the FDA has recommended that no new patients should be treated with the combination of olaratumab plus doxorubicin, following the negative results of the phase III ANNOUNCE trial.

The agency's statement follows the January 2019 announcement that olaratumab plus doxorubicin missed the ANNOUNCE trial’s primary endpoint of overall survival and did not confirm a clinical benefit for patients with advanced or metastatic STS compared with standard doxorubicin. The OS endpoint in the leiomyosarcoma subpopulation was also not met.

Moreover, the European Medicines Agency issued a similar recommendation based on the negative findings of the confirmatory trial, also stating that the combination of olaratumab and doxorubicin should not be administered in any new patients with advanced STS.

Both regulatory authorities made statements recommending that patients currently receiving olaratumab may continue to receive the treatment if they appear to be benefitting from it.

Results of ANNOUNCE, which was the confirmatory trial for the FDA approval of olaratumab in this setting, showed that there was no difference in OS between the 2 arms. The median OS was 20.4 months with olaratumab/doxorubicin and 19.7 months with doxorubicin. In the leiomyosarcoma subpopulation, the median OS was 21.6 months and 21.9 months for olaratumab/doxorubicin and doxorubicin, respectively.

*********************************

The FDA has placed a partial clinical hold on the phase III AIM2CERV trial exploring the use of axalimogene filolisbac in patients with high-risk locally advanced cervical cancer.

The communication from the agency cites that the partial hold has been put in place until additional information on chemistry, manufacturing, and control matters associated with AXAL, are received. There were no safety issues associated with the trial cited. Additionally, all patients currently enrolled will continue to receive treatment with the agent. However, no new patients can enroll in the trial until the hold is resolved.

Advaxis, the manufacturer of the immunotherapy agent, stated that it has already taken steps to provide the FDA with the requested information on AXAL in an effort to get the hold lifted in a timely manner.

In July 2018, the FDA previously lifted a clinical hold on a phase I/II study of AXAL in combination with durvalumab in patients with advanced, recurrent, or refractory cervical cancer and human papillomavirus-associated head and neck cancer.

The hold was initiated in March 2018 following a patient death related to acute respiratory failure after 9 months of AXAL treatment. Following the hold, Advaxis agreed to new guidelines for the early detection and treatment of rare adverse events, acute respiratory failure.

*********************************

In non–small cell lung cancer, Bristol-Myers Squibb withdrew its supplemental biologics license application for the combination of nivolumab and ipilimumab for the frontline treatment of patients with advanced disease with tumor mutational burden at least 10 mutations per megabase, following recent discussions with the FDA.

The agency initially accepted the application in June 2018 based on findings from the phase III CheckMate-227 trial, which showed that the 1-year progression-free survival rate was 43% for patients with high TMB assigned to the immunotherapy combination compared with 13% for those assigned to platinum-doublet chemotherapy.

In October 2018, BMS submitted an exploratory overall survival analysis to the FDA from part 1 of the CheckMate-227 trial, which included a low TMB subgroup of patients with stage IV or recurrent NSCLC who had not received prior therapy.

With these updated data, the FDA extended the review period by 3 months, which made the new action date May 20, 2019. However, the new data showed no difference in survival outcomes between patients whose tumors had high or low levels of TMB.

*************************************

The European Commission has approved an expanded indication for maintenance rucaparib in adult patients with platinum-sensitive, relapsed, high-grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA status.

The decision is based on findings from the phase III ARIEL3 trial, in which rucaparib led to an investigator-assessed median progression-free survival of 10.8 months compared with 5.4 months with placebo across the entire study population. Also, the overall response rate with rucaparib was 18%.

Additional results showed that, in patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo. The median PFS with rucaparib in this population was 16.6 months versus 5.4 months with placebo. Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency or low to high loss of heterozygosity.

The FDA approved the PARP inhibitor in this setting in April 2018, also based on the ARIEL3 findings.

*********************************

This week, we sat down with Dr Neha Mehta-Shah, of the Washington University School of Medicine in St. Louis, to discuss peripheral T-cell lymphoma treatment and future directions.